Skip to main content
SpringerLink
Log in

Cellular energetics and mitochondrial uncoupling in canine aging

  • Original Article
  • Published:
GeroScience Aims and scope Submit manuscript

Abstract

The first domesticated companion animal, the dog, is currently represented by over 190 unique breeds. Across these numerous breeds, dogs have exceptional variation in lifespan (inversely correlated with body size), presenting an opportunity to discover longevity-determining traits. We performed a genome-wide association study on 4169 canines representing 110 breeds and identified novel candidate regulators of longevity. Interestingly, known functions within the identified genes included control of coat phenotypes such as hair length, as well as mitochondrial properties, suggesting that thermoregulation and mitochondrial bioenergetics play a role in lifespan variation. Using primary dermal fibroblasts, we investigated mitochondrial properties of short-lived (large) and long-lived (small) dog breeds. We found that cells from long-lived breeds have more uncoupled mitochondria, less electron escape, greater respiration, and capacity for respiration. Moreover, our data suggest that long-lived breeds have higher rates of catabolism and β-oxidation, likely to meet elevated respiration and electron demand of their uncoupled mitochondria. Conversely, cells of short-lived (large) breeds may accumulate amino acids and fatty acid derivatives, which are likely used for biosynthesis and growth. We hypothesize that the uncoupled metabolic profile of long-lived breeds likely stems from their smaller size, reduced volume-to-surface area ratio, and therefore a greater need for thermogenesis. The uncoupled energetics of long-lived breeds lowers reactive oxygen species levels, promotes cellular stress tolerance, and may even prevent stiffening of the actin cytoskeleton. We propose that these cellular characteristics delay tissue dysfunction, disease, and death in long-lived dog breeds, contributing to canine aging diversity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • An J, Muoio DM, Shiota M, Fujimoto Y, Cline GW, Shulman GI, Koves TR, Stevens R, Millington D, Newgard CB (2004) Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat Med 10:268–274

    Article  CAS  PubMed  Google Scholar 

  • Baffy G, Derdak Z, Robson SC (2011) Mitochondrial recoupling: a novel therapeutic strategy for cancer? Br J Cancer 105:469–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Botigue LR, Song S, Scheu A, Gopalan S, Pendleton AL, Oetjens M, Taravella AM, Seregely T, Zeeb-Lanz A, Arbogast RM, Bobo D, Daly K, Unterlander M, Burger J, Kidd JM, Veeramah KR (2017) Ancient European dog genomes reveal continuity since the Early Neolithic. Nat Commun 8:16082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brand MD (2000) Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp Gerontol 35:811–820

    Article  CAS  PubMed  Google Scholar 

  • Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ, Miwa S, Pakay JL, Parker N (2004) Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med 37:755–767

    Article  CAS  PubMed  Google Scholar 

  • Cadieu E, Neff MW, Quignon P, Walsh K, Chase K, Parker HG, Vonholdt BM, Rhue A, Boyko A, Byers A, Wong A, Mosher DS, Elkahloun AG, Spady TC, Andre C, Lark KG, Cargill M, Bustamante CD, Wayne RK, Ostrander EA (2009) Coat variation in the domestic dog is governed by variants in three genes. Science. 326:150–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caldeira da Silva CC, Cerqueira FM, Barbosa LF, Medeiros MH, Kowaltowski AJ (2008) Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity. Aging Cell 7:552–560

    Article  CAS  PubMed  Google Scholar 

  • Cho SY, Seo DB, Kim WG, Lee SJ (2014) Mild mitochondrial uncoupling prevents premature senescence in human dermal fibroblasts. J Invest Dermatol 134:540–543

    Article  CAS  PubMed  Google Scholar 

  • Domanskyi S, Nicholatos JW, Schilling JE, Privman V, Libert S (2017) SIRT6 knockout cells resist apoptosis initiation but not progression: a computational method to evaluate the progression of apoptosis. Apoptosis. 22:1336–1343

    Article  PubMed  Google Scholar 

  • Ferrara CT, Wang P, Neto EC, Stevens RD, Bain JR, Wenner BR, Ilkayeva OR, Keller MP, Blasiole DA, Kendziorski C, Yandell BS, Newgard CB, Attie AD (2008) Genetic networks of liver metabolism revealed by integration of metabolic and transcriptional profiling. PLoS Genet 4:e1000034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fick LJ, Fick GH, Li Z, Cao E, Bao B, Heffelfinger D, Parker HG, Ostrander EA, Riabowol K (2012) Telomere length correlates with life span of dog breeds. Cell Rep 2:1530–1536

    Article  CAS  PubMed  Google Scholar 

  • Greer KA, Canterberry SC, Murphy KE (2007) Statistical analysis regarding the effects of height and weight on life span of the domestic dog. Res Vet Sci 82:208–214

    Article  PubMed  Google Scholar 

  • Greer KA, Hughes LM, Masternak MM (2011) Connecting serum IGF-1, body size, and age in the domestic dog. Age (Dordr) 33:475–483

    Article  CAS  Google Scholar 

  • Harper JM, Wang M, Galecki AT, Ro J, Williams JB, Miller RA (2011) Fibroblasts from long-lived bird species are resistant to multiple forms of stress. J Exp Biol 214:1902–1910

    Article  PubMed  PubMed Central  Google Scholar 

  • Hayward JJ, Castelhano MG, Oliveira KC, Corey E, Balkman C, Baxter TL, Casal ML, Center SA, Fang M, Garrison SJ, Kalla SE, Korniliev P, Kotlikoff MI, Moise NS, Shannon LM, Simpson KW, Sutter NB, Todhunter RJ, Boyko AR (2016) Complex disease and phenotype mapping in the domestic dog. Nat Commun 7:10460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoeflich A, Reyer A, Ohde D, Schindler N, Brenmoehl J, Spitschak M, Langhammer M, Tuchscherer A, Wirthgen E, Renner-Muller I, Wanke R, Metzger F, Bielohuby M, Wolf E (2016) Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD-deficient IGFBP-2 variant in female transgenic mice. Aging Cell 15:111–117

    Article  CAS  PubMed  Google Scholar 

  • Hoffman JM, Creevy KE, Franks A, O'Neill DG, Promislow DEL (2018) The companion dog as a model for human aging and mortality. Aging Cell 17:e12737

  • Housley DJE, Venta PJ (2006) The long and the short of it: evidence that FGF5 is a major determinant of canine ‘hair’-itability. Anim Genet 37:309–315

    Article  CAS  PubMed  Google Scholar 

  • Jensen MV, Joseph JW, Ilkayeva O, Burgess S, Lu D, Ronnebaum SM, Odegaard M, Becker TC, Sherry AD, Newgard CB (2006) Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion. J Biol Chem 281:22342–22351

    Article  CAS  PubMed  Google Scholar 

  • Jimenez AG, Winward J, Beattie U, Cipolli W (2018) Cellular metabolism and oxidative stress as a possible determinant for longevity in small breed and large breed dogs. PLoS One 13:e0195832

  • Kaeberlein M, Creevy KE, Promislow DE (2016) The dog aging project: translational geroscience in companion animals. Mamm Genome 27:279–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kraus C, Pavard S, Promislow DE (2013) The size-life span trade-off decomposed: why large dogs die young. Am Nat 181:492–505

    Article  PubMed  Google Scholar 

  • Lloyd AJ, Beckmann M, Tailliart K, Brown WY, Draper J, Allaway D (2016) Characterisation of the main drivers of intra- and inter- breed variability in the plasma metabolome of dogs. Metabolomics. 12:72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lloyd AJ, Beckmann M, Wilson T, Tailliart K, Allaway D, Draper J (2017) Ultra high performance liquid chromatography-high resolution mass spectrometry plasma lipidomics can distinguish between canine breeds despite uncontrolled environmental variability and non-standardized diets. Metabolomics 13:15

  • McCoin CS, Knotts TA, Ono-Moore KD, Oort PJ, Adams SH (2015) Long-chain acylcarnitines activate cell stress and myokine release in C2C12 myotubes: calcium-dependent and -independent effects. Am J Physiol Endocrinol Metab 308:E990–E1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Metsalu T, Vilo J (2015) ClustVis: a web tool for visualizing clustering of multivariate data using principal component analysis and heatmap. Nucleic Acids Res 43:W566–W570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Middleton RP, Lacroix S, Scott-Boyer MP, Dordevic N, Kennedy AD, Slusky AR, Carayol J, Petzinger-Germain C, Beloshapka A, Kaput J (2017) Metabolic differences between dogs of different body sizes. J Nutr Metab 2017:1–11

    Article  CAS  Google Scholar 

  • Mookerjee SA, Divakaruni AS, Jastroch M, Brand MD (2010) Mitochondrial uncoupling and lifespan. Mech Ageing Dev 131:463–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murakami S, Salmon A, Miller RA (2003) Multiplex stress resistance in cells from long-lived dwarf mice. FASEB J 17:1565–1566

    Article  CAS  PubMed  Google Scholar 

  • National Research Council (U.S.). Ad Hoc Committee on Dog and Cat Nutrition (2006) Nutrient requirements of dogs and cats. National Academies Press, Washington, D.C

    Google Scholar 

  • Redman LM, Smith SR, Burton JH, Martin CK, Il’yasova D, Ravussin E (2018) Metabolic slowing and reduced oxidative damage with sustained caloric restriction support the rate of living and oxidative damage theories of aging. Cell Metab 27:805–815 e804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rose G, Crocco P, De Rango F, Montesanto A, Passarino G (2011) Further support to the uncoupling-to-survive theory: the genetic variation of human UCP genes is associated with longevity. PLoS One 6:e29650

  • Sanderson SL, Simon AK (2017) In aged primary T cells, mitochondrial stress contributes to telomere attrition measured by a novel imaging flow cytometry assay. Aging Cell 16:1234–1243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shannon LM, Boyko RH, Castelhano M, Corey E, Hayward JJ, McLean C, White ME, Abi Said M, Anita BA, Bondjengo NI, Calero J, Galov A, Hedimbi M, Imam B, Khalap R, Lally D, Masta A, Oliveira KC, Perez L, Randall J, Tam NM, Trujillo-Cornejo FJ, Valeriano C, Sutter NB, Todhunter RJ, Bustamante CD, Boyko AR (2015) Genetic structure in village dogs reveals a Central Asian domestication origin. Proc Natl Acad Sci U S A 112:13639–13644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Speakman JR, van Acker A, Harper EJ (2003) Age-related changes in the metabolism and body composition of three dog breeds and their relationship to life expectancy. Aging Cell 2:265–275

    Article  CAS  PubMed  Google Scholar 

  • Speakman JR, Talbot DA, Selman C, Snart S, McLaren JS, Redman P, Krol E, Jackson DM, Johnson MS, Brand MD (2004) Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell 3:87–95

    Article  CAS  PubMed  Google Scholar 

  • Sukumar M, Liu J, Mehta GU, Patel SJ, Roychoudhuri R, Crompton JG, Klebanoff CA, Ji Y, Li P, Yu Z, Whitehill GD, Clever D, Eil RL, Palmer DC, Mitra S, Rao M, Keyvanfar K, Schrump DS, Wang E, Marincola FM, Gattinoni L, Leonard WJ, Muranski P, Finkel T, Restifo NP (2016) Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy. Cell Metab 23:63–76

    Article  CAS  PubMed  Google Scholar 

  • Sutter NB, Bustamante CD, Chase K, Gray MM, Zhao KY, Zhu L, Padhukasahasram B, Karlins E, Davis S, Jones PG, Quignon P, Johnson GS, Parker HG, Fretwell N, Mosher DS, Lawler DF, Satyaraj E, Nordborg M, Lark KG, Wayne RK, Ostrander EA (2007) A single IGF1 allele is a major determinant of small size in dogs. Science. 316:112–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang M, Miller RA (2012) Fibroblasts from long-lived mutant mice exhibit increased autophagy and lower TOR activity after nutrient deprivation or oxidative stress. Aging Cell 11:668–674

    Article  CAS  PubMed  Google Scholar 

  • Wang GD, Zhai W, Yang HC, Fan RX, Cao X, Zhong L, Wang L, Liu F, Wu H, Cheng LG, Poyarkov AD, Poyarkov NA Jr, Tang SS, Zhao WM, Gao Y, Lv XM, Irwin DM, Savolainen P, Wu CI, Zhang YP (2013) The genomics of selection in dogs and the parallel evolution between dogs and humans. Nat Commun 4:1860

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

J.W.N and J.D.Y thank Siri who is a good dog (12 out of 10). We also thank the NVIDIA Corporation for their donation of the Titan Xp GPU used in this work. Lastly, we thank the Cornell Veterinary Bank for primary canine fibroblast donations, as well as William Kohler and Melissa Han of the Miller lab for fibroblast preparations.

Funding

S.L. and J.W.N. were in part supported by a grant from the American Federation for Aging Research (AFAR, grant no. 2015-030). S.L. received seed grant funding from the Cornell University Center for Vertebrate Genomics. J.W.N. was supported by a Glenn/AFAR Scholarship for Research in the Biology of Aging. R.A.M was supported by the National Institute of Health grant U19-AG023122. I.S. group was supported by the National Science Foundation grant CMMI 1435655.

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences, Cornell University, Ithaca, NY, 14850, USA

    Justin W. Nicholatos, Timothy M. Robinette, Saurabh V.P. Tata, Jennifer D. Yordy, Adam B. Francisco, Michael Platov, Tiffany K. Yeh, Adam R. Boyko & Sergiy Libert

  2. Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC, 27701, USA

    Olga R. Ilkayeva, Frank K. Huynh & Matthew D. Hirschey

  3. Department of Mechanical Engineering, Tufts University, Medford, MA, 02155, USA

    Maxim Dokukin, Dmytro Volkov & Igor Sokolov

  4. Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA

    Michael A. Weinstein & Igor Sokolov

  5. Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA

    Richard A. Miller

Authors
  1. Justin W. Nicholatos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Timothy M. Robinette
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saurabh V.P. Tata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jennifer D. Yordy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Adam B. Francisco
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Platov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tiffany K. Yeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Olga R. Ilkayeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Frank K. Huynh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maxim Dokukin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dmytro Volkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael A. Weinstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Adam R. Boyko
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Richard A. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Igor Sokolov
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Matthew D. Hirschey
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Sergiy Libert
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, J.W.N. and S.L. Formal analysis, J.W.N. Investigation, J.W.N., M.P., T.M.R., S.V.T., A.B.F., J.D.Y., T.K.Y., D.V., M.W., F.K.H., and O.R.I. Writing—original draft—J.W.N. Writing—review and editing—J.W.N., T.M.R., J.D.Y., T.K.Y., I.S., M.D.H., and S.L. Supervision, S.L. Funding acquisition, J.W.N. and S.L.

Corresponding authors

Correspondence to Justin W. Nicholatos or Sergiy Libert.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Supplemental File 1

Supplemental Figs. 1–4 & Methods. Fig. S1 Acylcarnitine profiles have strong predictive power for canine breed. Fig. S2 PCA plot for all metabolites. Fig. S3 Fibroblasts from long-lived dog breeds may have a more flexible cytoskeleton than those from short-lived. Fig. S4 IGF-1 expression in primary fibroblasts is not different across breeds. (DOCX 1285 kb)

Supplemental File 2

Mass spectrometry raw data (XLSX 4537 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nicholatos, J.W., Robinette, T.M., Tata, S.V. et al. Cellular energetics and mitochondrial uncoupling in canine aging. GeroScience 41, 229–242 (2019). https://doi.org/10.1007/s11357-019-00062-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-019-00062-6

Keywords

Search

Navigation